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bioRxiv · 10.1101/2024.01.08.574702

Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease

Son, G.-Y.·Zou, A.·Wahl, A.·Huang, K. T.·Vinu, M.·Zorgit, S.·Zhou, F.·Wagner, L.·Idaghdour, Y.·Yule, D. I.·Feske, S.·Lacruz, R. S.
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Abstract

Sjogrens disease (SjD) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been involved in the development of SjD. Saliva production is regulated by parasympathetic input into the glands initiating intracellular Ca2+ signals that activate the store operated Ca2+ entry (SOCE) pathway eliciting sustained Ca2+ influx. SOCE is mediated by the STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel. However, there are no studies on the effects of lack of STIM1/2 function in salivary acini in animal models and its impact on SjD. Here we report that male and female mice lacking Stim1 and Stim2 (Stim1/2K14Cre) in salivary glands showed reduced intracellular Ca2+ levels via SOCE in parotid acini and hyposalivate upon pilocarpine stimulation. Bulk RNASeq of the parotid glands of Stim1/2K14Cre mice showed a decrease in the expression of Stim1/2 but no other Ca2+ associated genes mediating saliva fluid secretion. SOCE was however functionally required for the activation of the Ca2+ activated chloride channel ANO1. Despite hyposalivation, ageing Stim1/2K14Cre mice showed no evidence of lymphocytic infiltration in the glands or elevated levels of SSA or SSB autoantibodies in the serum, which may be linked to the downregulation of the toll-like receptor 8 (Tlr8). By contrast, salivary gland biopsies of SjD patients showed increased STIM1 and TLR8 expression, and induction of SOCE in a salivary gland cell line increased the expression of TLR8. Our data demonstrate that SOCE is an important activator of ANO1 function and saliva fluid secretion in salivary glands. They also provide a novel link between SOCE and TLR8 signaling which may explain why loss of SOCE does not result in SjD.

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Son, G.-Y., Zou, A., Wahl, A., Huang, K. T., Vinu, M., Zorgit, S., Zhou, F., Wagner, L., Idaghdour, Y., Yule, D. I., Feske, S., Lacruz, R. S.. 2024-01-08. Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease. https://doi.org/10.1101/2024.01.08.574702

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